Inhaled Amikacin Versus Placebo in Patients With Ventilator-associated Tracheobronchitis

Официальное название

A Multicentre, Double-blind, Randomized Controlled Trial of Inhaled Amikacin Versus Placebo in Critically Ill Patients With Ventilator-associated Tracheobronchitis

Обзор

The primary objective of the AMIVAT trial is to assess whether a 5-day course of inhaled amikacin, compared to placebo, reduces the incidence of progression to ventilator-associated pneumonia (VAP) at day 28 in intensive care unit (ICU) patients with ventilator-associated tracheobronchitis (VAT). Transition from VAT to VAP will be defined as the occurrence of a first VAP episode due to the same pathogens than those responsible for VAT.

Подробное описание

VAT will be defined using the following criteria: (i) duration of mechanical ventilation \> 48 hours, (ii) purulent tracheobronchial secretions, (iii) no new or progressive persistent pulmonary infiltrate on chest X-ray, and (iv) bacterial growth on endotracheal aspirate (ETA) ≥10.5 colony-forming unit (CFU)/mL or on bronchoalveolar lavage ≥10.4 CFU/mL or on plugging telescopic catheter ≥10.3 CFU/mL. Inclusion and randomization will be performed after written informed consent, as soon as inclusion criteria are met, within 24 hours after VAT suspicion (ETA sampling) whenever possible. Patients in the experimental group will receive inhaled amikacin (once daily, 20 mg/kg of predicted body weight with a maximum of 2 grams) from Day 1 (inclusion, randomization and first nebulization) to Day 5 through an optimized and protocolized nebulization procedure (vibrating mesh nebulizer). Patients in the control group will receive inhaled placebo (NaCl 0.9%, once daily) from Day 1 (inclusion, randomization and first nebulization) to Day 5 through an optimized and protocolized nebulization procedure (vibrating mesh nebulizer). Nebulization will be performed according to a standardized procedure using a vibrating mesh nebulizer (Aerogen Solo, Aerogen, Galway, Ireland). A bedside checklist will be used to ensure optimal implementation practice. All staff involved in nebulization will be trained prior to their study involvement. The systemic diffusion and pharmacokinetics of inhaled amikacin will be assessed through measurement of peak and residual blood concentrations in a pre-planned subsample of patients. Study treatment will be discontinued before the 5th administration in the following cases: (i) documented acquired amikacin resistance in at least one pathogen responsible for VAT, (ii) occurrence of VAP before Day 5, (iii) occurrence of AKI stage 2 or 3 of the KDIGO classification before Day 5 (except for patients receiving renal replacement therapy), (iv) clinical indication for mandatory IV aminoglycoside therapy (amikacin, gentamicin, tobramycin) before Day 5, (v) extubation before Day 5, (vi) unexpected SAE deemed related to the IP and/or a patient's clinical condition that requires suspension of the treatment according to the local investigator. Patients will be followed-up until Day 28 for the primary study endpoint and up to Day 90 for certain secondary study endpoints (Day-90 mortality, and day-90 health-related quality of life \[HRQoL\] in survivors).

Вмешательства

• Препарат Optimized and protocolized nebulization procedure.
  Patients in the experimental group will receive inhaled amikacin (once daily, 20 mg/kg of predicted body weight with a maximum of 2 grams) from Day 1 (inclusion, randomization and first nebulization) to Day 5 through an optimized and protocolized nebulization procedure (vibrating mesh nebulizer).
• Препарат Optimized and protocolized nebulization procedure.
  Patients in the control group will receive inhaled placebo (NaCl 0.9%, once daily) from Day 1 (inclusion, randomization and first nebulization) to Day 5 through an optimized and protocolized nebulization procedure (vibrating mesh nebulizer).

Первичные конечные точки

• Incidence of transition from ventilator-associated tracheobronchitis to ventilator-associated pneumonia at day 28 [Срок оценки: From randomization to day 28]

Вторичные конечные точки (12)

• Incidence of transition from ventilator-associated tracheobronchitis to ventilator-associated pneumonia at day 7 [Срок оценки: From randomization to day 7]
• Overall incidence of a first ventilator-associated pneumonia episode (all pathogens) at day 28 [Срок оценки: From randomization to day 28]
• Overall incidence of a first ventilator-associated pneumonia episode due to multidrug-resistant bacteria at day 28 [Срок оценки: From randomization to day 28]
• Time to resolution of clinical signs of ventilator-associated tracheobronchitis [Срок оценки: From randomization to day 28]
• Proportion of patients with persistence of the pathogens responsible for ventilator-associated tracheobronchitis on endotracheal aspirate at day 7 [Срок оценки: Day 7]
• Total duration of mechanical ventilation [Срок оценки: From randomization to day 90]
• Number of ventilator-free days at day 28 [Срок оценки: From randomization to day 28]
• The number of days with systemic antibiotics at Day 28 [Срок оценки: From randomization to day 28]
• Number of defined daily doses of systemic antibiotics at day 28 [Срок оценки: From randomization to day 28]
• Incidence of intensive care unit-acquired intestinal colonization with multidrug-resistant bacteria at day 28 [Срок оценки: From randomization to day 28]
• Overall incidence of Intensive care unit-acquired infection due to multidrug-resistant bacteria at day 28 [Срок оценки: From randomization to day 28]
• Lenght of stay in the intensive care unit [Срок оценки: From randomization to day 90]

Критерии участия

Критерии включения

• Age ≥ 18 years
• Admission to a participating intensive care unit (ICU)
• Invasive mechanical ventilation > 48 hours
• First episode of ventilator-associated tracheobronchitis during the ICU stay defined using the following criteria: (i) purulent tracheobronchial secretions, (iii) no new or progressive persistent pulmonary infiltrate on chest X-ray, and (iv) bacterial growth on endotracheal aspirate ≥10.5 colony-forming unit (CFU)/mL or on bronchoalveolar lavage ≥10.4 CFU/mL or on plugging telescopic catheter ≥10.3 CFU/mL
• Coverage by the French health insurance system (Social Security)
• Written informed consent obtained from the patient, or, if the patient is not able to give written consent, from his or her legally designated representative (trusted person designated by the patient or, failing that, a family member) or, failing that, inclusion performed by the investigator within the therapeutic window (in such cases, informed consent will be sought by the investigator from the patient, or his or her legally designated representative, whichever is sooner). In all cases, the patient's written informed consent will be obtained as soon as possible.
• For woman of childbearing potential: negative pregnancy test result at the time of inclusion

Критерии исключения

• Previous ventilator-associated pneumonia due to the pathogens responsible for ventilator-associated tracheobronchitis during the same ICU stay
• On-going antimicrobial therapy fpr ventilator-associated pneumonia
• Ventilator-associated tracheobronchitis due to pathogens with intrinsic amikacin resistance (e.g. Stenotrophomonas maltophilia)
• On-going therapy with intravenous amikacin or another aminoglycoside
• Acute kidney injury stage 2 or 3 of the Kidney Disease Improving Global Outcomes (KDIGO) classification and/or advanced chronic kidney failure (glomerular filtration rate <30 mL/min), except in patients under renal replacement therapy
• Grade B or C cirrhosis (Child-Pugh classification)
• Scheduled extubation within 24h
• Prior tracheotomy
• Administration of inhaled antibiotics within the 7 preceding days
• Known hypersensitivity to amikacin, another aminoglycoside, or any of the excipients
• Myasthenia gravis
• Contraindication to nebulization
• On-going treatment with ataluren
• Persons covered by articles L1121-5 to L1121-8 of the French Public Health Code (corresponding to all protected persons: pregnant women, parturients, nursing mothers, persons deprived of their liberty by judicial or administrative decision, minors, and persons subject to a legal protection measure: guardianship or trusteeship).
• Moribund patient
• End-of-life decision
• Previous inclusion in the present study
• Participation to another interventional study
• Inability of the patient, or the person providing consent, to understand all aspects of the research
• Patient being a relative of the investigator or a relative of someone from the team directly involved in the trial, including doctors and pharmacists

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Франция · 17 центров

• 06 - ANGERS - Intensive care, University Hospital — Angers
• 04 - ARGENTEUIL - Intensive care, University Hospital — Argenteuil
• 11 - BLOIS, Intensive care, Hospital — Blois
• 09 - BOURG-EN-BRESSE, Intensive care, Hospital — Bourg-en-Bresse
• 10 - HENRI MONDOR, Intensive care, University Hospital — Créteil
• 07 - DIEPPE - Intensive care, University Hospital — Dieppe
• 08 - DIJON - Intensive care, University Hospital — Dijon
• 12 - DREUX, Intensive care, Hospital — Dreux
• … и ещё 9 центров

Идентификаторы

NCT: NCT07665788 · DR230005 · 2023-510075-63-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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